1. Field of the Invention
The present invention relates to the preparation of molding materials having certain bioactive functions, special measures in the processing of these molding materials to provide articles having surface-active bioactive functions and the use of these articles in medical technology, in particular for contact with blood or components thereof.
2. Description of the Related Art
The term "bioactivity" is to be understood herein in the widest sense as meaning the interaction between certain randomly arranged functional groups or combinations of such functional groups in synthetically produced macromolecules and complementary functions of natural macromolecular systems.
The interaction between blood and foreign surfaces, for example polymer surfaces, is well-known. The contact of certain proteins contained in the blood with these foreign surfaces leads to a cascade-like activation of various biochemical secondary reactions which culminate in the so-called complement activation or blood coagulation. Since the 1950s, a wide range of detailed experiments have been carried out in an attempt to influence the interaction between foreign surfaces and blood so that, on temporary or on long-term contact, blood coagulation and disadvantageous reactions of the immune system, such as inflammations, etc., do not occur.
The range of measures is wide and in some cases contradictory, as shown in the following review, c.f. R. Barbucci et al. "Modifications of Polymer Surfaces to Improve Blood Compatibility", page 119 et seq. in: Polymeric Biomaterials, S. Dumitriu Editor, Marcel Dekker Inc., 1994:
(1) Establishment of hydrophobic surfaces PA0 (2) Production of surfaces having a zwitterionic or anionic structure PA0 (1) The reproducible establishment of identical bioactive surfaces, for example for series production of catheters and blood bags, which is indispensable in human medicine, cannot be guaranteed in this manner. PA0 (2) The subsequent modification is time-consuming and consumptive of material (economy and ecology). PA0 (3) The reusability (recycling) of such surface-modified articles is not possible because the same bioactive surfaces will not be present after a further melting and processing step. PA0 (1) Coating or lining of heat-resistant materials, such as metal alloys or plastics (crosslinked or uncrosslinked), such as, for example, phenol/formaldehyde condensates, nylon-4, nylon-6, nylon-6,6 or ceramic substances, and PA0 (2) Production of continuous water/steam gliding film.
hydrophobic surfaces after alkylation, hence preferred adsorption of albumin, hence reduction of blood coagulation, PA1 imparting of hydrophilic properties to polymer surfaces with polyethylene glycol chains, hence reduced protein and blood platelet adsorption; PA1 neutral zwitterionic structures, e.g., polymer-bound phosphorylcholine end groups (EP 0 275 295, 1986, A. A. Durrani), PA1 anionic structures of certain concentration and composition. PA1 M--F.sub.1, PA1 M--F.sub.2, PA1 M--F.sub.3, and PA1 M--F.sub.1 -F.sub.4, PA1 M is a radical of the hydrophilic monomer and: PA1 F.sub.1 is an alkyl, aryl or alkyl/arylhydroxyl group, PA1 F.sub.2 is an alkyl, aryl or alkyl/arylcarboxyl group, PA1 F.sub.3 is an alkyl, aryl or alkyl/arysulfonyl group, and PA1 F.sub.4 is an alkyl, aryl or alkyl/arylphosphatyl group. PA1 M--F.sub.2 --S.sub.1, PA1 M--F.sub.3 --S.sub.1, PA1 M--F.sub.1 -F.sub.4 --S.sub.1, PA1 M--F.sub.1 -F.sub.4 --S.sub.2, and PA1 M--F.sub.1 -F.sub.4 --S.sub.3, PA1 K--F.sub.1, PA1 K--F.sub.2, PA1 K--F.sub.3, PA1 K--F.sub.1 -F.sub.4, PA1 K--F.sub.2 --S.sub.1, PA1 K--F.sub.3 --S.sub.1, PA1 K--F.sub.1 -F.sub.4 --S.sub.1, PA1 K--F.sub.1 -F.sub.4 --S.sub.2, and PA1 K--F.sub.1 -F.sub.4 --S.sub.3, PA1 3 wash cycles of 3 hours with 1.5 molar NaCl at 90.degree. C. PA1 3 wash cycles of 3 hours with water at room temperature PA1 1 wash cycle of 12 hours with Michaelis buffer at room temperature
The measures according to the invention follow this last-mentioned line of development.
Here, the naturally occurring heparin, a glycosamine glycan having carboxyl, sulfate and aminosulfate groups, has long been preferred. It was bound adsorptively, ionically or covalently to polymer surfaces; however, it was found that its activity declines relatively rapidly and hence the stability required for long-term clinical applications is no longer present. A further development consisted in fixing the heparin functions recognized as bioactive, namely carboxylate and sulfate/sulfonate, to the surfaces of a range of crosslinked polymers or to dissolved polymers by wet chemical polymer-analogous reactions, in order to produce heparin-like behavior in this manner. The work of Jozefowicz and Jozefowicz et al. may be mentioned in particular here, cf. EP-A 0 023 854, 0 090 100, 0 094 893, 0 201 378, 0 203 865 and 0 304 377.
Polymer surfaces can be modified in the manner described above also with the aid of energy sources, such as ionizing radiation or electrical discharges, cf. R. Barbucci et al. loc. cit., page 204 et seq.
Finally, it is also possible to introduce the bioactive functions bound to vinyl monomers into polymer systems by copolymerization or to bind them in a thin polymer layer to polymer surfaces. Examples of this line of development are works by Miller, Sawyer et al., J. Appl. Polym. Sci. 1970, 14, 257-266, by Sorm, Nespurek et al., J. Polym. Sci., Polym. Symp. 1979, 66 349-356, and EP 0 598 486 to MEDTRONIC Inc. (Oct. 14, 1993). In this more recent application, combinations of the monomeric acrylic acid and 2-acrylamido-2-methylpropanesulfonic acid, in particular in a molar ratio of 2:7, are claimed. This monomer mixture is either copolymerized as such and then applied to polymer surfaces, for example by immersion in corresponding solutions, or it is grafted directly onto polymer surfaces in the presence of cerium ions.
A common feature of all processes mentioned, where they relate to solid polymers and surfaces thereof, is that the bioactive functions are fixed to already shaped articles in a further processing step. The disadvantages of such processes are obvious:
Accordingly, there remains a need for a process which overcomes these disadvantages.